The long-range goal of this research is to establish the role of uterine macrophaages in promoting maternal immunological acceptance of the fetus. Following mating, macrophages migrate into the uterus, become activated and subsequently produce copious prostaglandin E2 (PGE2). Because PGE-2 profoundly inhibits lymphocyte proliferation, this macrophage product contributes importantly to establishment of the immunosuppressive environment that protects the embryo from destruction by maternal immune cells. The environmental forces responsible for channeling uterine macrophages into this highly desirable state are not known, but preliminary studies indicate that the steroidal hormones of pregnancy, estrogens and progesterone, and/or hormonally stimulated polypeptide growth factors may have major roles. The products of three genes, interferon-gamma (IFN-gamma), IFN-gamma receptors (IFN- gammaR) and inducible prostaglandin G/H synthase (PGHS-2) are central to macrophage activation and production of PGE2. Thus, the Specific Aims of this application are as follows: Aim 1, to (a) identify cellular sources of IFN-gamma mRNA and protein in cycling and pregnant mice and (b) ascertain relationships between IFN- gamma in mouse uterus and levels of estrogens and progesterone; Aim 2, to determine the direct and indirect influences of estrogens and progesterone on IFN-gammaR gene expression in mouse macrophages; Aim 3, to establish the direct and indirect influences of estrogens and progesterone on activation of mouse macrophages for PGE2 synthesis. Contemporary techniques of molecular and cellular biology that include northern and in situ hybridization, nuclear run- on experiments, transient transfection assays, electrophoretic mobility assays, western blotting, immunohistochemistry, flow cytometry, ELISA and cell culture will be used. These studies are expected to (1) illuminate the mechanisms underlying hormonal regulation of a critical uterine macrophage function, immunosuppression, thus enhancing our understanding of how the environment appropriate to semiallogeneic pregnancy is established, (2) supply data essential to designing therapeutic strategies for women whose suboptimal reproductive performance has an immunological component, and (3) because hormones target macrophages in all organs and tissues, provide crucial new information on how female sex steroid hormones control immune competence in women of child bearing age.